1. Field of the Invention
The present invention relates to a pharmaceutical composition containing a pyrylium compound, thiopyrylium compound, selenopyrylium compound or telluropyrylium compound (hereafter referred to as "a pyrylium compound") or a salt of any of the aforesaid compounds as active ingredient. It also provides a method for the treatment of the human and animal body which comprises administering the compound to a human or animal and irradiating a locus in said animal where the compound is absorbed in order to kill cells at that locus. It further comprises the use of the aforesaid compound for making a medicament for use in the treatment of cancer in humans and animals.
2. Related Art
In the pharmaceutical field, one of the most important problems is to find medicaments for use in the treatment of cancer. One approach to the treatment of cancer is to use photochemistry. Extensive research has been carried out into the photochemical treatment of cancer, and it has been put into clinical use since 1976. There is an extensive journal and patent literature concerning photochemical treatments for cancer, see for example the general remarks of Michael J. Manya (J. Clin. Oncology, vol. 6, 1988, pp. 380-391). In these literature and patent references almost all the medicaments which have been adminstered to enable photochemical treatment to be carried out contain a porphyrin compound, particularly hematoporphyrin derivatives (HPD) or diamatoporphyrin derivatives (DHE) which have been applied clinically, and a medicament called PHOTOFRIN which contains DHE is expected to be marketed shortly by LEDERLE JAPAN Co. Ltd.
The way in which photochemical treatment is carried out using a medicament containing a porphyrin-type compound will now be explained. When this medicament is given to a patient suffering from cancer, then almost all the active material is metabolised by normal cells in a few days (48 to 72 hours). However, medicament absorbed by cancer cells is not metabolised, and the amount thereof that builds up in the cell is from several times to several tens of times that in a normal cell. Then the cancer cells and surrounding tissue is irradiated with light of frequency 600-700 nm, and the cancer cells in which the medicament has built up die preferentially whilst normal cells are generally unaffected by the radiation. Accordingly, it is possible to treat cancer in this way without producing unacceptable side effects. The reason why the medicament remains preferentially in the cancer cells is not clear, but it is believed to be the result of a difference in blood circulation between the cancer cells and normal cells. It is also not clear why cancer cells in which the medicament is present die when subject to irradiation. However, it is believed that radiant energy absorbed by the medicament brings about transformation of oxygen in the vicinity of the cancer cells into singlet oxygen which has strong cytotoxicity.
The photochemical method of treatment has some problems, one of which is the mismatch of the wavelength at which the porphyrin-type compound absorbs light and the wavelength of the radiation which can be used. For irradiating cells it is desirable to use radiation having a wavelength from 600 nm to near infrared. The first reason is that it is necessary for the radiation to penetrate into the living tissue. For example, in the case of a skin cancer the radiation should penetrate the skin to a depth of several millimeters. Radiation of 600 nm wavelength or less is absorbed or scattered by substances in the living body and does not penetrate to the desired depth. The second reason is that it is necessary to avoid any radiation damage to the hemoglobin in red blood corpuscles. Oxidised hemoglobin has adsorption peaks at 540 nm and 577 nm and reduced hemoglobin has an absorption peak at 555 nm. The energy of the radiation used for irradiation treatment is so strong that when a living body is irradiated with light of wavelength 500-600 nm, hemoglobin is damaged. Furthermore, it is undesirable to use for treatment radiation having a wavelength of 1200 nm or above because that radiation brings about heating of the living tissue.
For the above reasons it is apparent it is necessary to use for treatment radiation having a wavelength of 600-1000 nm. However, DHE has a maximum absorption peak at 363 nm and at wavelengths of 600 nm or above, DHE has an absorption of only 2-3% of the peak (.epsilon. 630 nm=3.6.times.10.sup.3 l/mol.cm; W. Roberts et al, J. Natl. Cancer Inst., vol. 80, 1988, pp. 330-336). Therefore the absorption of the light used for treatment is inefficient and it is necessary to increase the amount of medicament to be administered or to increase the intensity of the irradiating light. This requires expensive apparatus for the treatment, and give rise to harmful after-effects.
Various investigations have been made with the object of overcoming these problems. For example, Japanese laid open Patent Application JP-A-1-275528 discloses porphyrin-type compounds which have been modified to extend their absorption wavelength and to increase their strength of absorption. The compound exhibiting the strongest absorption has an extinction coefficient .epsilon. of 2.24.times.10.sup.4 l/mol.cm to 630 nm wavelength. This patent also discloses a further type of compounds whose absorption strength is stronger. However, it does not disclose that these compounds exhibit anti-tumor characteristics.
In a paper written by W. Roberts a method is disclosed for synthesising a compound having an absorption peak with an extinction coefficient of 3.8.times.10.sup.4 l/mol.cm at 630 nm wavelength. However, in order to improve the efficiency of the treatment, a medicament having an absorption peak at longer wavelengths and having a greater extinction coefficient is desired.
According to Nikkan Kogyo Shimbun on Jun. 7, 1993, further research on MONOASPARTYLCHLORIN by Nippon Sekiyu Kagaku K.K., on PHEOPHORBIDE by Hamari Yakuhin Kogyo K.K., on ZINCFLIN by Asahi Kasei Kogyo K.K. were reported. However, these compounds are still in the research stage, and almost all the investigations now being carried out concern porphyrin-type compounds whose mode of action on cancer cells is as described above.
Titanium dioxide has been investigated as an anti-cancer medicament whose mode of action on cancer cells differs from medicaments based on porphyrin-type compounds. However, in this approach there is a difficulty in transporting the titanium dioxide selectively to the cancer cells and ultraviolet radiation is required for treatment.